title: The inhibition of death receptor mediated apoptosis through lysosome stabilization following internalization of carboxyfullerene nanoparticles.
abstract: Cells undergo apoptosis through two major pathways, the extrinsic pathway (death receptor pathway) and the intrinsic pathway (the mitochondrial pathway). It is well known that nanomaterials of water- soluble fullerene derivatives are potent antioxidants and help to prevent the overproduction of mitochondrial reactive oxygen species (ROS). However, whether their interaction with cells via the death receptor pathway is direct or indirect remains poorly understood. Here, we show that a bis-adduct malonic acid derivative of fullerene, C₆₀(C(COOH)₂)₂, inhibits tumor necrosis factor alpha-initiated cellular apoptosis via stabilizing lysosomes. Data presented here demonstrate that nano-sized aggregates of this water-soluble fullerene derivative are endocytosed into cells and enriched in the lysosomes. During the internalization of C₆₀(C(COOH)₂)₂, the expression of Hsp 70 is significantly upregulated, promoting cell survival by inhibiting the permeabilization of lysosomal membranes. In addition, the acidic environment inside lysosomes has a marked but temporary effect on the size distribution of fullerenic nanoparticles, and may disperse the aggregated C₆₀(C(COOH)₂)₂ nanoparticles into single molecules or smaller aggregates. These single molecules or smaller aggregates may insert into the lysosomal membranes, further stabilizing them and decreasing the release of cathepsins from lysosomes, leading to the inhibition of tumor necrosis factor-induced apoptosis. C₆₀(C(COOH)₂)₂ nanoparticles can thus protect cells by stabilizing lysosomal membranes via both upregulated expression of Hsp 70 and by their interactions with lysosomal membranes.
authors.affiliation: CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and National Center for Nanoscience and Technology, Chinese Academy of Sciences (CAS), Beijing 100049, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Taotao
authors.initials: T
authors.lastname: Wei
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002264:Carboxylic Acids / Q000009:adverse effects / Q000737:chemistry*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D050884:HSP72 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain